(a) Field of the Invention
The invention relates to a method of evaluating the efficacy of drugs on brain nerve cells based on the use of proton magnetic resonance spectroscopy.
(b) Description of Prior Art
Amyotrophic lateral sclerosis (ALS) is a progressive, usually sporadic form of motor neuron disease (MND) affecting both the upper motor neurons (UMNs) and the lower motor neurons (LMNs). The motor neurons are the postulated primary targets of the disease process. The relationship of MNDs involving solely the UMNs (primary lateral sclerosis (PLS)) or LMNs (progressive spinal muscular atrophy (PSMA)) with ALS remains to be established. Pure LMN syndromes may be present in hexosaminidase deficiency and immune-associated syndromes which, in some cases, may be amenable to specific therapies.
Magnetic resonance spectroscopy (MRS.) is similar to conventional magnetic resonance imaging (MRI), and is performed using basically the same equipment with relatively minor hardware and software modifications. However, whereas MRI provides anatomical information based on signals from water, MRS. Prides chemical information from metabolites That are present in tissues at much lower concentration than water.
Proton magnetic resonance spectroscopic imaging (1H-MRS.) Prides the ability to noninvasively evaluate regional chemical pathology of human brain in vivo. Proton MR spectra of human brain reveal two signals of interest for this application: a signal from N-acetyl groups (mainly N-acetylaspartate) (NAA) and a signal from creatine (Cr). NAA is found exclusively in neurons and neuronal processes in the normal mature brain (Moffett J R, Namboodiri M A A, Cangro C B, Neale J H, 1991, NeuroReport, 2:131-134; simmons M L, Frondoza C G, Coyle J T, 1991, Neuroscience, 45:37-45) and, thus, can be used as a marker of neuronal integrity. Cr is present in all cells of the brain and can be used as an internal standard. The expression of NAA signal intensity relative to Cr (NAA/Cr) allows for easy comparison of NAA signal intensity (and, by implication, neuronal integrity) between different subjects.
1H-MRS can be used to assess and monitor the evolution of neuronal or axonal damage in various conditions, including MS, stroke, human immunodeficiency virus-associated cognitive impairment and Alzheimer""s disease.
A major problem in assessing drug efficacy in neurodegenerative disease is the lack of efficient clinical outcome measures. As a result of this, large multicenter trials are generally necessary. Such trials cost many millions of dollars, and may produce negative results, as did recent trial of ciliary neuronotropic factor and brain-derived neuronotropic factor. An efficient surrogate marker of efficacy would, therefore, be extremely valuable.
MRS has been used for a number of years now to assess neuronal and axonal loss based on the signal intensity of N-acetyl groups, which comes primarily from NAA in brain. The Applicants have used the signal to quantify the severity of disease and follow its progression based on decreases in NAA over time. Recently, we have reported the fact that decreases in NAA can spontaneously recover with time after certain brain injuries (multiple sclerosis relapses and some kinds of stroke). (De Stefano N, Matthews P M, Arnold D L, 1995, Magn. Reson. Med., 34:721-727).
However, to date there exist no means to assess in vivo whether a drug has any positive effect on the brain function of a patient, such as restoring its NAA signal.
In accordance with the present invention, the Applicants have now discovered that abnormally low NAA levels can made to increase with effective drug therapy in patients with amyotrophic lateral sclerosis (ALS). This indicates that NAA can be used as a marker of improved neuronal function as well as a marker of neuronal loss. The use of MRS to measure increases in NAA as a marker of drug efficacy is novel and provides unexpected and unprecedented results.
In accordance with the present invention there is provided a method to measure in vivo the effect of a drug on the function of the brain of a patient suffering from a neurologic disease, which comprises the steps of:
a) obtaining 1H-MR spectra of the brain of the patient and measuring the signals from NAA;
b) subjecting the patient to a treatment with the drug to be tested and measuring the signals from NAA in the brain of the patient; and
c) comparing the spectra of steps a) and b) to determine whether the drug has an effect on the function of nerves cells in the brain; whereby the increase in the NAA signal of step b) is indicative of a drug with a positive effect.
The term xe2x80x9cneurologic diseasesxe2x80x9d when used herein is intended to mean, any neurologic diseases including strokes, multiple sclerosis, amyotrophic lateral sclerosis, epilepsy and neurodegenerative diseases such as Alzheimer""s disease among others.
This invention can also be used to monitor drug improvement produced by treatment of other neurodegenerative diseases for which NAA decline has been observed with disease progression (such as Alzheimer""s disease). Moreover, spontaneous improvement with time in NAA observed in certain types of cerebrovascular insults, and in acute exacerbations of multiple sclerosis (D L. Arnold et al., 1992, Proc. Soc. Magn. Reson. Med., 1:643; N. De Stefano et al., 1995, Neurology, 45:1193-1198; N. De Stefano et al., 1995, Magn. Reson. Med., 34:721-727) also indicate that drug therapies for these disorders may be tested in MRSI to assay for more complete or more rapid NAA recovery with novel drug therapies. This invention will help identify agents useful to human neurological therapeutics before the initiation of full scale clinical trials, and will help identify dosing regiments that may be most effective in such clinical trials.